R. Michael Tuttle, MD: Along those same lines, Frank, from a practical approach, it seems like you oncologists always start stuff really high, apologize, and back down. Endocrinologists start low, and we raise the dose. Help me understand this. Should we really be starting at the max dose of any of these drugs or should we start lower? How do we think about that?

Frank Worden, MD: Right. So, I personally look at the fact that—especially with lenvatinib—if you’re going for response, that if somebody comes in with pretty extensive disease or disease that I want to try to retain the best response, I’ll start with the highest dose. And, as I mentioned earlier, I’ll follow them back weekly to see. It doesn’t mean I’m not going to reduce the dose if we have to, if there’s intolerability and we can’t control the hypertension despite various antihypertensive agents, etc. But I believe that to attain the best chance for a response, you really have to start with the highest dose and then you adjust accordingly. It’s the same thing with sorafenib. If you start low and try to work your way up—and we’ve done that—in my own anecdotal experience, I don’t see the benefit. And Marcia, I think we’ve talked about this, too.

Marcia S. Brose, MD, PhD: Well, I think we definitely have seen in anecdotal experiences that there does seem to be a dose–response relationship. So, if you want to get the results that were seen in the clinical trials, you have to follow the way the clinical trial was done. As Frank keeps alluding to, when he goes back, he goes back to the same dose initially because sometimes it could clear up and you don’t necessarily have to decrease the dose. And so, if you can try that once or twice, if it’s not working, then you can decrease the dose. But let’s be aware of the fact that in the trials, the average dose of sorafenib was 650 mg. So, about half of the patients had needed at least one dose reduction. In my experience, if you go to two dose reductions, you’re more likely to start having escape. If somebody had a response and you go down to 400 mg/day, you’re more likely to have creeping up of the disease.

So, we do everything we can, and that is harder for an oncologist, to really work to keep those side effects down. You have to put time and you have to put nursing support and resources into it; it’s always easy just to decrease the dose. Sure, you can get rid of the side effects, but you’ll also get rid of the benefit. It’s also important to note that in the SELECT study, the average dose went down to about 16 mg, and so the starting dose was 24 mg. That’s two to three doses down. And now, there are additional studies going forward to decide whether or not in that situation, you dose reduce. Because 40% of patients had grade 3/4, which is very high. Mostly it was grade 3, but that was quite a large increase in blood pressure and did quite often lead to headaches and symptoms from that. I think that it’s important for us to know, do we really need to reduce? But that will be answered actually in the context of a clinical trial and outside of data saying it works just as well. We also always start at the high dose.

R. Michael Tuttle, MD: We’re uniformly going for the high dose and trying to help tolerate.

Naifa Busaidy, MD, FACP, FACE: I’m just going to play devil’s advocate, maybe just only because I come from the endocrine background, as you pointed out. But we know the majority of the patients are not going to tolerate the 24 mg for long. And in the SELECT trial, the vast majority were dose reduced very early on. There were a few that tolerated the full dose, but it’s early on. I think one could see both sides. I’m one to prefer to start at a higher dose, as well, but there are those patients who–—given their comorbidities and their disease burden—you do worry that they’re not going to tolerate it. And so we have started plenty of patients at 10 mg and 14 mg that have had very nice responses. So, just like Marcia said, that I think we don’t know.

Marcia S. Brose, MD, PhD: Some of those patents may not have even been eligible for the trial.

Naifa Busaidy, MD, FACP, FACE: For the trial, absolutely.

Marcia S. Brose, MD, PhD: So, when you’re outside of patients who would have been on the trial, I think you have to customize it for sure.

Frank Worden, MD: Absolutely.

Marcia S. Brose, MD, PhD: But if the patient would have been otherwise eligible for a trial, I don’t think...You have to be aware that when you go off script, you may not get the results. It may not matter if it’s not symptomatic, but I think it’s important. I’m a purist when it comes to that, unless I have a reason—again, a guideline—but with a reason, I will do something different.

Frank Worden, MD: I think that’s how I do it, too. If I want to try to retain that response, I try to go for the gusto with the biggest dose. But I agree with you: if you look at somebody and there really isn’t a response needed per se that I need to shrink something down, I may start at 10 mg or 14 mg.

Transcript Edited for Clarity

Transcript:

R. Michael Tuttle, MD: Along those same lines, Frank, from a practical approach, it seems like you oncologists always start stuff really high, apologize, and back down. Endocrinologists start low, and we raise the dose. Help me understand this. Should we really be starting at the max dose of any of these drugs or should we start lower? How do we think about that?

Frank Worden, MD: Right. So, I personally look at the fact that—especially with lenvatinib—if you’re going for response, that if somebody comes in with pretty extensive disease or disease that I want to try to retain the best response, I’ll start with the highest dose. And, as I mentioned earlier, I’ll follow them back weekly to see. It doesn’t mean I’m not going to reduce the dose if we have to, if there’s intolerability and we can’t control the hypertension despite various antihypertensive agents, etc. But I believe that to attain the best chance for a response, you really have to start with the highest dose and then you adjust accordingly. It’s the same thing with sorafenib. If you start low and try to work your way up—and we’ve done that—in my own anecdotal experience, I don’t see the benefit. And Marcia, I think we’ve talked about this, too.

Marcia S. Brose, MD, PhD: Well, I think we definitely have seen in anecdotal experiences that there does seem to be a dose–response relationship. So, if you want to get the results that were seen in the clinical trials, you have to follow the way the clinical trial was done. As Frank keeps alluding to, when he goes back, he goes back to the same dose initially because sometimes it could clear up and you don’t necessarily have to decrease the dose. And so, if you can try that once or twice, if it’s not working, then you can decrease the dose. But let’s be aware of the fact that in the trials, the average dose of sorafenib was 650 mg. So, about half of the patients had needed at least one dose reduction. In my experience, if you go to two dose reductions, you’re more likely to start having escape. If somebody had a response and you go down to 400 mg/day, you’re more likely to have creeping up of the disease.

So, we do everything we can, and that is harder for an oncologist, to really work to keep those side effects down. You have to put time and you have to put nursing support and resources into it; it’s always easy just to decrease the dose. Sure, you can get rid of the side effects, but you’ll also get rid of the benefit. It’s also important to note that in the SELECT study, the average dose went down to about 16 mg, and so the starting dose was 24 mg. That’s two to three doses down. And now, there are additional studies going forward to decide whether or not in that situation, you dose reduce. Because 40% of patients had grade 3/4, which is very high. Mostly it was grade 3, but that was quite a large increase in blood pressure and did quite often lead to headaches and symptoms from that. I think that it’s important for us to know, do we really need to reduce? But that will be answered actually in the context of a clinical trial and outside of data saying it works just as well. We also always start at the high dose.

R. Michael Tuttle, MD: We’re uniformly going for the high dose and trying to help tolerate.

Naifa Busaidy, MD, FACP, FACE: I’m just going to play devil’s advocate, maybe just only because I come from the endocrine background, as you pointed out. But we know the majority of the patients are not going to tolerate the 24 mg for long. And in the SELECT trial, the vast majority were dose reduced very early on. There were a few that tolerated the full dose, but it’s early on. I think one could see both sides. I’m one to prefer to start at a higher dose, as well, but there are those patients who–—given their comorbidities and their disease burden—you do worry that they’re not going to tolerate it. And so we have started plenty of patients at 10 mg and 14 mg that have had very nice responses. So, just like Marcia said, that I think we don’t know.

Marcia S. Brose, MD, PhD: Some of those patents may not have even been eligible for the trial.

Naifa Busaidy, MD, FACP, FACE: For the trial, absolutely.

Marcia S. Brose, MD, PhD: So, when you’re outside of patients who would have been on the trial, I think you have to customize it for sure.

Frank Worden, MD: Absolutely.

Marcia S. Brose, MD, PhD: But if the patient would have been otherwise eligible for a trial, I don’t think...You have to be aware that when you go off script, you may not get the results. It may not matter if it’s not symptomatic, but I think it’s important. I’m a purist when it comes to that, unless I have a reason—again, a guideline—but with a reason, I will do something different.

Frank Worden, MD: I think that’s how I do it, too. If I want to try to retain that response, I try to go for the gusto with the biggest dose. But I agree with you: if you look at somebody and there really isn’t a response needed per se that I need to shrink something down, I may start at 10 mg or 14 mg.